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Original Articles: Pediatric Cardiac

Role of Natriuretic Peptides in cGMP Production in Fetal Cardiac Bypass

^a Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
^b Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio
^c Department of Surgery, University of Cincinnati, Cincinnati, Ohio

Accepted for publication December 5, 2008.

^_* Address correspondence to Dr Eghtesady, Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039 (Email: Pirooz.Eghtesady{at}cchmc.org).

Presented at the Poster Session of the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background: We previously showed cyclic guanosine 3',5'-monophosphate (cGMP) levels increase with fetal cardiac bypass despite derangements in the placental nitric oxide pathway. The natriuretic peptides, atrial (ANP), brain (BNP), and c-type (CNP), are common indicators of cardiac distress, and an alternative pathway for cGMP generation. We hypothesized that these natriuretic peptides may account for the paradoxic rise in cGMP seen with fetal bypass.

Methods: Six ovine fetuses, 106 to 118 days' gestation, underwent cardiac bypass for 30 minutes and were followed for 120 minutes after bypass. Fetal plasma samples were collected before bypass, during bypass, and 30 and 120 minutes after bypass for natriuretic peptide analysis. Results were compared with 6 sham bypass fetuses and cGMP values from another 14 bypass fetuses (to avoid confounding effects of excess blood sampling). Fetal hemodynamics and metabolics were correlated to ANP, BNP, and CNP values. Statistical analysis was by analysis of variance, Student's t test, and best-fit correlations, with significance set at p = 0.05 or less.

Results: The ANP, BNP, and CNP increased with fetal bypass (674 ± 133 pg/mL, 151 ± 52 pg/mL, and 295 ± 45 pg/mL, respectively), remaining elevated after bypass, whereas sham concentrations remained stable at pre-bypass levels. Changes in ANP, BNP, and CNP positively correlated with rising cGMP. There was positive correlation between ANP and CNP and rising fetal lactate levels, but not to other physiologic parameters associated with placental dysfunction.

Conclusions: There is a substantial rise in natriuretic peptides seen with fetal bypass, likely in part a reflection of myocardial dysfunction. Further, the natriuretic peptide pathway may account for the paradoxic rise in cGMP seen with fetal bypass.

	Introduction

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The placental dysfunction reported after fetal cardiac surgery is of unknown etiology [1–6] but has led to immense interest in vasoactive substances and associated pathways whose disruption might be an underlying cause of elevated placental vascular resistance. Disruption of nitric oxide (NO) production, which stimulates cyclic guanosine 3',5'-monophospate (cGMP) in vascular smooth muscle leading to vasodilatation, has been implicated in the placental dysfunction of fetal bypass. The same pathway has been implicated in pulmonary dysfunction in neonatal bypass models [3, 7]. Natriuretic peptides, however, also stimulate cGMP synthesis through a similar, but alternative pathway [8].

When catalyzed with guanosine-5'-triphosphate, cGMP is directly synthesized by two different types of guanylate cyclase enzymes: soluble guanylate cyclase and particulate guanylate cyclase. As seen in Figure 1, endothelial NO synthase (eNOS), a source of NO in the placenta, forms NO through direct stimulation of soluble guanylate cyclase production [9]. Particulate guanylate cyclase, however, is activated when atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) bind to their specific natriuretic peptide membrane receptors [10]. The ANP and BNP are found mainly in the atria and ventricles, respectively [11, 12], and bind to particulate guanylate cyclase-A receptors [10]. The CNP is produced primarily from endothelial cells [13, 14], in a wide variety of tissues such as brain, reproductive, and skeletal tissues, and binds preferentially to the particulate guanylate cyclase-B receptor [10, 15]. Recent studies have suggested an important role for CNP in local endothelial-mediated vasoregulation of the adult heart [16, 17], and also the fetal lung vasculature [15]. Increased levels of ANP, BNP, and CNP have also been shown to correlate with the severity of cardiac distress in congestive heart failure [17–19], and in response to cardiopulmonary bypass in children [20–23].

View larger version (19K): [in this window] [in a new window]   Fig 1. This diagram depicts the cyclic guanosine 3',5'-monophosphate (cGMP) synthesis pathway through nitric oxide (NO) and natriuretic peptides. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) activate particulate guanylyl cyclase (pGC) through their respective receptors (pGC-A and pGC-B), and when catalyzed with guanosine triphosphate (GTP), form cGMP, leading to vasodilation. Nitric oxide derived from endothelial nitric oxide synthase (eNOS) activates soluble guanylyl cyclase (sGC), which also stimulates the synthesis of guanosine monophosphate (GMP), leading to vasodilation.

	Material and Methods

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Surgical Instrumentation
Time-dated singleton and twin pregnant ewes (n = 6 experimental; n = 6 controls), 106 to 118 days of gestation (111 ± 3 days of gestation, 1.9 ± 0.5 kg body weight) were used in this study. Using methods we have previously described, ewes were fasted 24 hours before sedation with ketamine and valium, intubated endotracheally, and placed on 2% isoflurane and oxygen for anesthesia [2, 3, 24]. Catheters were placed in the ewes' femoral artery for blood gas measurement and femoral vein for intravenous fluid delivery. After midline laparotomy and a small hysterotomy, catheters were placed in the fetal femoral artery and vein for blood gas measurements and blood sampling, respectively. Through the same hysterotomy, an umbilical flow probe (Transonic Systems, Ithaca, NY) was placed to measure placental blood flow. Hemodynamic values were continuously recorded using a PowerLab data acquisition system (AD Instruments, Colorado Springs, CO), as described previously [2, 3, 24]. To address any potential unfound effects of sternotomy on natriuretic peptide levels, the experimental protocol was performed with a sternotomy in some control animals (n = 2) and experimental animals (n = 4). For the conduct of bypass, all fetuses were cannulated in the right jugular vein and the right carotid artery, as described previously [2, 3, 24]. The control group underwent all surgical procedures and cannulation, but the animals were not placed on bypass. All procedures were performed in accordance with Institutional Animal Care and Use Committee procedures in an Association for Assessment and Accreditation of Laboratory Animal Care–approved facility and complied with the "Guide for the Care and Use of Laboratory Animals" (National Research Council, 1996).

Fetal Bypass
Based on our previous studies [2, 3, 24], our target flow rate during bypass was 200 to 250 mL · min^–1 · kg^–1 with fetal weights estimated during surgery. The pump system was normothermic and nonpulsatile, consisting of a roller pump with vacuum-assisted drainage, heat exchanger, the placenta as sole oxygenator, and the circuit primed with blood from an adult donor ewe other than the mother [2, 3, 24]. Bypass lasted for 30 minutes, and fetuses were monitored after bypass for 120 minutes. Ewes and fetus were then euthanized for autopsy, tissue collection, fetal morphometrics, and confirmation of catheter positions.

Sampling Regimen
Fetal arterial blood was collected before and after neck cannulation, at 15 and 30 minutes of bypass, and at 30, 60, 90, and 120 minutes after bypass for determination of blood gases, using an i-STAT clinical analyzer (i-STAT Corp, Windsor, NJ), and glucose and lactate values, using a YSI 2300-STAT analyzer (YSI Corp, Yellow Springs, OH). Fetal blood samples for immunoassay were collected before bypass, at 30 minutes of bypass, and 30 and 120 minutes after bypass into lithium heparin-coated tubes (Monovettes; Sarstedt, Newton, NC), and were immediately placed on ice, centrifuged, and the separated plasma frozen at –20°C until assayed.

ANP, BNP, and CNP Immunoassays
The ANP, BNP, and CNP levels in fetal plasma were determined using competitive enzyme-linked immunosorbent assays (ELISA [Phoenix Pharmaceutical, Burlingame, CA]) [25]. Natriuretic peptide levels were correlated to cGMP levels from another group of 14 fetuses [3], to avoid detrimental effects of excessive blood sampling, measured with ELISA (Cayman Chemicals, Ann Arbor, MI). All immunoassay results were read on a Multiskan EX microplate reader (Thermo EC, Waltham, MA) using Ascent software (Thermo EC) for data handling and analysis.

Statistical Analysis
To determine differences in measured parameters, data were analyzed using Student's t test and type III analysis of variance with least significant difference post-hoc analysis, with p of 0.05 or less defined as statistically significant. Data are reported as mean ± SD. Correlation coefficients were determined using mean values and regression lines with best fit.

	Results

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Placental Gas Exchange and Fetal Hemodynamics
Fetal arterial blood gas values and hemodynamics with the conduct of fetal cardiopulmonary bypass are shown in Table 1. As reported previously [1–4, 24], fetal bypass increases pCO₂ and lactate levels, followed by declining pO₂, pH (mixed acidosis) and placental blood flow, and coincident elevation of placental vascular resistance.

View larger version (20K): [in this window] [in a new window]   Fig 2. Timeline summary for fetal plasma levels of atrial natriuretic peptide (ANP [triangles]), brain natriuretic peptide (BNP [squares]), and C-type natriuretic peptide (CNP [circles]) and cyclic guanosine 3',5'-monophosphate (cGMP [dashed line]) shown as percent change from sham controls. Levels of all four variables were significantly elevated compared with controls.

Fetal Plasma CNP
As for ANP and BNP, pre-bypass levels of CNP were similar for control and bypass fetuses, although substantially higher than what has been reported in the unstressed fetus. Although not as robust of a response, still bypass led to increases in CNP concentrations by 42% during 30 minutes of bypass (295 ± 45 pg/mL, p = 0.036); the CNP levels remained elevated at 30 minutes (p = 0.025) and 120 minutes (p = 0.020) after bypass (Table 2). The CNP levels for control animals showed no changes. When compared with controls, animals exposed to bypass had significantly higher CNP concentrations at 30 minutes (p < 0.01) and 120 minutes (p < 0.01) after bypass (Fig 2) and overall (p < 0.01; Fig 2).

Natriuretic Peptide Correlations to cGMP
We had previously shown that rising cGMP levels are inversely proportional to the rise in placental vascular resistance after fetal bypass [3]. To assess the role of natriuretic peptides in fetal bypass and the associated rise in cGMP levels, correlations were derived between average plasma levels of cGMP and natriuretic peptides at each time point. Bypass elevates fetal ANP, BNP, and CNP levels, which positively correlated with rising cGMP levels (R² = 0.52, 0.61 and 0.64, respectively; Table 3). For control animals, ANP and CNP did not correlate with cGMP; however, BNP negatively correlated with cGMP concentrations (Table 3).

	Comment

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Natriuretic peptides have previously been studied in conjunction with pediatric and adult cardiac bypass procedures. Our experiment represents the first time this important family of vasoactive compounds has been studied in fetal bypass, a procedure complicated by morbid placental dysfunction. This study shows a significant increase in fetal plasma levels of ANP, BNP, and CNP during and after bypass. The rise in these natriuretic peptides appears to correlate with the paradoxic rise in cGMP that we have noted before [3]. The substantial rise in these natriuretic peptides does not correlate with physiologic factors associated with fetal bypass and are also not sufficient to overcome the associated rise in placental vascular resistance seen with bypass, despite their known vasodilatory properties.

The rise in the natriuretic peptides appears to occur rather early in the experimental protocol, indeed, to some extent before initiation of extracorporeal circulation. Most prominently, ANP levels are increased after 30 minutes of fetal bypass, remaining elevated throughout the post-bypass period. Similar to ANP, although of lesser magnitude, BNP and CNP also increase during bypass and after bypass. Of note, in contrast to BNP and CNP, ANP is stored in granules, which allows a rapid response to even the smallest stimuli [26], which may in part explain the larger and earlier response seen with ANP. With the onset of bypass, fetal blood volume is diluted with adult donor blood from the bypass circuit. That could result in either spurious elevations of measured concentrations (if significantly higher load of natriuretic peptide is added) or significant underestimation of levels (from hemodilution). Our group and others [25, 27] have reported fetal ANP levels that are fairly equivalent, and BNP and CNP levels that are slightly higher than maternal blood, whereas others have reported lower levels in maternal blood [28–31]. Assuming the worse-case scenario, the slightly higher levels, however, are still much lower than the elevated fetal levels reported here. Prior studies have shown that maternal natriuretic peptides cannot cross the placental circulation to alter measured fetal values [27, 32]. Therefore, our results are likely an underestimate of natriuretic responses because of hemodilution of the fetal circulation from donor prime blood, an inherent limitation of our model.

Natriuretic peptides play an important role in volume homeostasis, renal function, and control of blood pressure through their function as vasodilators and are released primarily in response to stretching of the myocardial tissue and an increase in intracardiac pressure or volume overload, or both [16, 33–35], namely, in the setting of myocardial "stress" as occurs acutely with cardiopulmonary bypass or chronically with heart failure. Numerous studies evaluating ANP and BNP changes during human cardiopulmonary bypass report conflicting results. One study indicates that plasma ANP concentrations decrease after 30 minutes of pediatric cardiopulmonary bypass (and immediately increase after cessation of bypass) [22], to levels significantly lower than in this study at the same time point (52 ± 44 pg/mL versus 674 ± 144 pg/mL, respectively). Atinou and colleagues [21] showed that plasma ANP and BNP concentrations in children decrease with sternotomy and bypass, and continue to decline after bypass. In sharp contrast, other studies report a decrease of ANP levels in children and after bypass while BNP levels increased during the same period [20, 23], which is more similar to our experience with fetal bypass. It should be noted, however, that these clinical studies involve abnormal hearts, as opposed to our studies that use normal fetal hearts, making direct comparison less applicable. We observed no effect of sternotomy on natriuretic peptide levels.

The heart is typically empty when on cardiopulmonary bypass, and since there is presumably no volume overload or myocardial stretching, a decrease in ANP concentrations during bypass might be expected. The fetal bypass model, however, does not result in a completely empty, beating heart (as evidenced by limited but continued pulsatile arterial tracings). Indeed, one of the unique properties of the fetal heart is the continued collateral return to the left atrium through presumed bronchopulmonary or aortopulmonary collaterals as evidenced by the simultaneous presence of an empty right atrium and somewhat distended left atrium/left ventricle. That the fetal sheep anatomy includes an unusual communication of a left-sided azygous system directly into the coronary sinus only makes this process more complex [36]. It is of further interest that other investigators have shown a unique distribution of natriuretic peptide concentrations in the fetal sheep circulation, with significantly higher concentrations of ANP and BNP secretion within the coronary sinus effluent [37]. During fetal bypass, these peptides might be redistributed, although one would expect an equilibration by 30 minutes of bypass perhaps. Nevertheless, overall volume status of the fetal heart (although not empty) does not change substantially during bypass, in contrast to the significant changes seen in natriuretic peptide levels.

Alternatively, there is a significant rise in fetal mean arterial pressure with onset of bypass, along with an associated rise in systemic and placental vascular resistance, that may create a substantial afterload to the immature myocardium [2]. This results in some decline of fetal cardiac output; the coincident increased afterload may in turn cause natriuretic peptide release [33, 34]. Of note, elevated vasoconstrictors and cytokines that contribute to increased afterload in the setting of fetal bypass are also associated with natriuretic peptide production or release [2, 4–6]. Thus, while reasons for natriuretic peptide increase in our model are likely multifactorial, insult or injury to the myocardium might play a critical role. The addition of intracardiac monitoring data to assess myocardial stretch during fetal bypass would be helpful and represents a potential future direction.

Increased levels of ANP, BNP, and CNP have also been shown to correlate with the severity of cardiac distress in congestive heart failure that is thought to be activated by neurohormonal mediators such as renin and angiotensin [16–20]. The renin-angiotension pathway is upregulated during fetal bypass [4], which along with our natriuretic peptide results suggest that the fetus may be experiencing a form of cardiac distress from bypass. Interestingly, in patients with congestive heart failure, it has been shown that vasodilatory responses to ANP are diminished [38]. A similar pathophysiologic mechanism might be occurring with fetal bypass, leading to a persistent rise in placental vascular resistance despite ANP elevations, in other words, no vasodilatory response to ANP in the constricted placental vasculature. Other in vivo studies suggest that at high concentrations, ANP acts as a vasoconstrictor [39, 40], an effect not noted for BNP or CNP. Of note, fetal ANP levels during bypass in this study were as much as four times higher than fetal baseline ANP values reported by us and others (674 ± 133 pg/mL versus 180 ± 44 pg/mL, respectively) [25, 31]. In addition, Sultainian and coworkers [40] showed that the postcapillary resistance in vasculature can be due to acute ANP increases, and that it could be blocked with a selective particulate guanylyl cyclase-A antagonist. Further studies incorporating administration of synthetic ANP or ANP receptor antagonists to the fetus would be needed to test this hypothesis in the ovine fetal bypass model.

Our study also shows significant alterations in CNP expression in the fetal vasculature with exposure to extracorporeal circulation. Previously reported CNP levels in the human and ovine fetal circulation are low (12 pg/mL and 53 pg/mL, respectively) [27, 29], yet we measured very high CNP concentrations in fetal plasma during and after bypass (approximately 300 pg/mL). If CNP values are usually low, the changes seen with bypass reflect a large activation of the CNP pathway. Coincidently, elevated cytokines are known to activate CNP production [14], and also characterize fetal bypass [5, 6]. Second, the fetus regulates CNP independently [27, 29] and separate from the maternal circulation, suggesting that the fetal endothelium is a direct production site of CNP, as reported in adult human and animal studies [14, 15]. Lastly, we and others have documented the profound increase in circulating levels of vasoconstrictors such as angiotensin-II, endothelins, and vasopressin with fetal bypass [2, 4, 5], suggesting a potential compensatory or reactive role for endothelial CNP secretion. Additional studies analyzing CNP and particulate guanylyl cyclase-B content in the fetal and placental vasculature would further characterize the fetal CNP response to bypass and offer insights into the CNP synthesis pathway and the mechanism of fetal vascular regulation.

In summary, we have shown that the natriuretic peptides are significantly elevated with fetal bypass and that this rise correlates with the simultaneous paradoxic rise in cGMP. The rise of the peptides did not, however, account for the rise in placental vascular resistance and was only correlated to rising lactate levels, a marker of inadequate tissue oxygen delivery, perhaps likely due to compromised myocardial function after fetal bypass. These studies may explain the paradoxic rise in cGMP seen with fetal bypass despite severe derangements of the NO pathway. Further, these results also suggest to us that perhaps cGMP is not the critical signaling mediator affected with placental dysfunction as seen with fetal bypass. Use of cGMP analogs and other manipulations of the pathway will allow us to answer these possibilities. Moreover, further studies analyzing guanylate cyclase activity would be needed to determine whether the soluble guanylyl cyclase pathway, stimulated by nitric oxide, or the particulate guanylyl cyclase pathway, stimulated by natriuretic peptides, are primarily responsible for the cGMP. Further examination of the autocrine/paracrine actions of CNP in the vascular endothelium of the fetus would also be of great interest.

	Acknowledgments

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The authors gratefully acknowledge the technical assistance of our perfusion colleagues Jerri Hilshorst and John Lombardi, and Robert Giulitto of Hoxworth Blood Center for donation of blood collection supplies. Our research is supported by grants from the American Heart Association National Scientist Development Grant (0535292N), Children's Heart Foundation of Chicago, and Children's Heart Association of Cincinnati.

	References

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